Aims

1
Clinical Pharmacology Therapeutics Stage III
lecture Treatment of Anaphylaxis

• Aims Objectives
• To describe the presentation and cellular basis
  for anaphylaxis
• Highlight important differentials that can mimic
  it
• Discuss in detail its drug management
• Introduce other hypersensitivity-based drug
  reactions

2
Treatment of Anaphylaxis

• No accepted definition
• A life threatening activation of mast cells and
  basophils
• Not necessarily type I hypersensitivity/IgE
  mediated
• Death from asphyxiation or cardiovascular
  collapse
• Incidence uncertain (probably heavily
  underreported)
• ? 12,300 AE admissions (115,000 general
  population/year)

3
Anaphylactic vs. Anaphylactoid reactions

• Anaphylactoid reactions mimic the features of an
  anaphylactic reaction but mast cell/basophil
  activation is not IgE-dependent.
• Certain drugs (and venoms) are able to directly
  activate mast cells including
• Succinylcholine
• Morphine
• Tubocurarine
• Vancomycin (Red-man Syndrome)
• N-acetyl-cysteine
• Treatment is the same as for Anaphylaxis.

4
Clinical Features of Anaphylaxis

• - Is there a predisposition? Latex and food
  allergies usually occur against a background of
  atopy and other allergic disorders e.g. asthma
  and eczema.
• - Onset is rapid (5-10 minutes of exposure)
  peaking in 30 minutes. Duration can be long
  especially if allergen persists (e.g. swallowed)
  or the response is biphasic (classical
  late-phase allergic response in the airways)
• - May be heralded by impending sense of doom.
  Subsequent features reflect to some extent route
  of allergen exposure
• Systemic (IV drugs) - cardiovascular
  (hypotension/syncope)
• Ingested (food allergens) - respiratory
  (laryngeal oedema/bronchoconstriction)
• Percutaneous (insect stings) - respiratory or
  cardiovascular problems equally likely
• All may be accompanied by cutaneous features
• e.g. urticarial rash.

Urticarial Rash
5
Features Suggesting Severe Anaphylactic Reaction

• Wheeze
• Stridor
• Cyanosis
• Skin Pallor
• Prominent Tachycardia

80 of fatal food-related anaphylactic
reactions have no skin signs Compared to
bradycardia in vasovagal attack
6
Anaphylactic Reactions Differential Diagnosis

• Anxiety (Panic Disorder)
• Asthma
• Epiglottitis
• Foreign body Inhalation
• AMI
• PE
• Vasovagal Attack

Wheeze/Stridor/SOB
Syncope/Collapse
but bradycardic NOT tachycardic
7
A real allergic response? Non-allergens and
hidden allergens

• Allergy to fish could be due any one of the
  following
• Histamine intoxication (Scombroidism)
• Dinoflagellate poisoning (algal blooms)
• Cod worm (Anisarkis) allergy
• Latex allergy (latex gloves used in food
  preparation)

8
Histamine the Mast cell

• Intradermal histamine produces the classical
  Triple response central red spot
  (vasodilatation) flare wheal (oedema overlying
  initial red spot).
• Intravenous histamine causes (1) marked
  vasodilatation (largely from endothelial derived
  NO) (2) increased capillary leak. These
  H1-mediated effects contract effective blood
  volume.
• Importance of mast cell-derived histamine in
  anaphylaxis depends on species tissue.
• In humans, protection offered by H1 blockade is
  variable
• oedema/itch - good
• hypotension - modest
• bronchoconstriction - negligible

9
2005 Guidelines of the UK Resuscitation Council
10
Effects of Adrenaline (Epinephrine)
Comparison of its cardiovascular effects (at
10?g/min IVI) with noradrenaline (?-dominant) and
isoprenaline (?2-dominant).

• Other important (if not crucial) ?2 effects
• Mast-cell stabilisation (against IgE activation)
• Bronchodilatation

11
The Use of Adrenaline in Anaphylaxis

• The problems with its use
• Variable Absorption - give IM AVOID SC
• Arrhythmogenic in high dose - NEVER give 11000
  ADRENALINE IV
• If using ADRENALINE as an IVI, it must be diluted
  and do not delay administration of ADRENALINE to
  set up IVI and gain IV access.
• Therefore
• 1. Give ADRENALINE IM promptly (can repeat at
  5-10 min intervals)
• 2. Gain IV access
• 3. If patient remains shocked resort to IVI thus
  .
• Dilute 0.5ml of 11000 ADRENALINE in 50ml
  of N/saline (1100,000)
• 4. Infuse at 0.1-2ml/min (1-20ug/min) until
  haemodynamically stable

12
Drugs that Interact with Adrenaline

• The effects of adrenaline are markedly
  potentiated in patients taking concurrent
  tricyclic antidepressants, MAOIs or cocaine.
• The ?-effects of adrenaline may also be
  antagonised (and the manifestations of
  anaphylaxis more severe) if the patient is taking
  concurrent ?-blockers (especially non-selective
  agents).
• Phenothiazines (especially chlorpromazine) are
  potent ?-blockers hence adrenaline may cause
  unexpected hypotension (unrestrained ?2-mediated
  vasodilatation).

13
Histamine (H1) receptor antagonists

• FIRST-GENERATION e.g Chlorpheniramine and
  Diphenhydramine
• sedating (although paradoxical excitation in
  overdose)
• anticholinergic effects
• SECOND- GENERATION e.g. Terfenadine and
  Cetirizine
• Non-sedating (poor CNS penetration)
• No anticholinergic effects
• Risk of VT (Torsade de Pointes) with Terfenadine
  and Astemizole
• Only chlorpheniramine has a preparation for
  systemic use
• but not licensed for IV administration!

This is a PK problem due to their clearance
through CYP 3A4/5. Drugs (e.g. erythromycin,
ketoconazole, or grapefruit juice) block
conversion of parent drug to the active H1
antagonist - the parent drugs block delayed
rectifier (K-current) in the heart prolonging QTc
I.e. behave like class III agents.
14
Other drugs used in Anaphylaxis
Nebulised or IV ?2 agonist (e.g. salbutamol) -
useful where bronchospasm is the major sign and
fails to respond promptly to IM adrenaline. IV
Glucocorticoid (e.g. hydrocortisone 200-500mg) -
probably of limited efficacy (onset of action
delayed 3-6 hrs) except where the response is
biphasic or asthmatic features predominate. IV
Glucagon (1mg in 1L, infused at 5-15ml/min) -
anecdotal reports of efficacy in refractory
hypotension. Releases catecholamines and ve
inotrope (raising cAMP independent of cardiac
?-adrenoceptors). H2 Antagonists - isolated
reports of increased efficacy of combined
blockade NB histamine relaxes VSM directly by H2
effect - this is slower in onset but much more
sustained than H1 effect on endothelial cells.
Efficacy in systemic mastocytosis clearer.
15
Further Ix and Management

• Collect (preferably within 1hr and NOT 6hr) 10ml
  of clotted blood for
• Mast Cell Tryptase assay (if diagnostic doubt
  exists)
• Assay of Allergen-Specific IgE levels (RAST).
• Refer to Allergist for
• Identification of allergen (RAST, skin-prick
  testing etc)
• Desensitisation (especially Bee/Wasp venoms)
• Assessment of need for Px of Epipen (Adrenaline
  autoinjector)

16
Drug-Induced Allergic Reactions

• Type I - IgE dependent. Needs previous exposure
  to allergize.
• Type II - Cytolytic IgG/M antibodies causing C
  activation. Usually fade with drug withdrawal.
  Form basis of
• Methyl-DOPA induced haemolysis
• Quinidine/Quinine-induced thrombocytopenia
• Sulphonamide-induced granulocytopenia
• Drug-induced lupus (hydralazine procainamide)
• Type III - Serum sickness (Arthus reaction).
  Deposition of C fixing IgG-Ag complexes in vessel
  wall produces urticaria, arthritis,
  lymphadenopathy and fever. Offenders include
• Antibiotics (sulphonamides and penicillin)
• Anticonvulsants (phenytoin and carbamazepine)
• Iodides.
• Also cause Steven-Johnson syndrome as a rare
  severe form of type III immune vasculitis.

17
Allergic reactions Angioedema

• Usually localised (to head neck) but may be
  more generalised (especially GI) /- urticaria.
• Presents as swelling of the face, neck and
  oropharynx.
• Represents mast cell degranulation in skin deep
  to dermis vs. superficial dermis in urticaria.
• Inherited - C1 esterase inhibitor deficiency due
  to mutation of the C1-INH gene (autosomal
  dominant).
• Acquired - usually autoantibodies to C1-INH in
  the context of autoimmune disease or
  lymphoproliferative disorders. Rarer reports of
  hypercatabolism of C1-INH in infection.
• Drug-induced - commonest culprit ACE inhibitors
  (and OMAPATRILAT).

18
ACE inhibitors Angioedema

• Mechanism probably related to massive elevation
  of BK but unclear why it can appear days to years
  after 1st dosing.
• Incidence probably renal/cardiac transplant patients may be at
  increased risk.
• Treatment is usually with standard therapy for
  an anaphylactic reaction /- inhaled Epi but not
  mast cell dependent! If airway threatened,
  intubation or tracheostomy needed.
• Under recognised especially in milder forms. ACE
  inhibitors should be stopped and an AT1 receptor
  antagonist substituted if necessary (e.g.
  Losartan) BUT isolated reports have appeared of
  angioedema with these agents!
• New combined ACE/NEP inhibitors suffer same
  problem.

19
Allergic Reactions to Penicillins

• Allergization often occult (food containing pen.
  or the pen. mould itself)
• Anti-pen antibodies are detectable in almost
  everyone
• Patients reports of previous allergy are
  frequently inaccurate
• A class problem manifesting as -
• Rash (MP urticarial)
• Fever
• Bronchospasm
• Vasculitis
• Serum sickness/Stevens-Johnson
• Anaphylaxis
• Rashes most frequent with ampicillin (10)
  essentially 100 in EBV infection.
• Rashes more likely if allopurinol
  co-administered
• Cross-sensitisation with cephalosporins now
  thought to be
• If pen drug-of-choice consider either
  controlled challenge or desensitisation
• VERY uncommon previously received it and of these only 1/3
  report previous reaction.

Frequency
20
Further Information

• Treatment algorithms in pdf format (Clin Pharm
  Website)
• Allergy section of E-medicine (www.emedicine.com/
  emerg)
• Resuscitation council - (http//www.resus.org.uk/
  pages/reaction.htm)